The objective of this proposal is the define the signal transduction pathways that mediate Interleukin 9 (IL-8) receptor regulation of cell function, specifically chemotaxis. The recruitment and activation of neurophilis by IL-8 has been implicated in the tissue damage and destruction of a variety of pulmonary diseases. Additionally, the recruitment of neurophils and/or other cell types by IL-8 may have a significant role in the control of malignant cell growth. Defining the signal transduction pathways and cellular functions stimulated by Il-8 will aid in an understanding of the role Il-8 has in lung disease and the control of malignant cell growth. To address this objective, the following specific aims will be carried out: 1a) determine the effect in human neutrophils of peptides which activate or inhibit the p85/p110 phosphatidylinositol-3-kinase (P13K); 1b) determine whether p38 is activated in response to Il-8 receptor activation; 2a) define and reconstitute, if necessary, the signal transduction pathways (phospholipase C, Ras/Raf/MAPK, P13K and p38-MARK) activated in neutrophils by Il-8 in Il- 8RB positive HEK-293 cells; 2b) define the signal transduction pathways required for coupling the Il-8 receptor to chemotaxis in HEK-293 cells using inhibitory and constitutive active mutants of p110-P13K, P13K-gamma, cdc42Hs, Rac,Ras and p38-MAPK.